Bevacizumab and platinum-based combinations for recurrent ovarian cancer: a randomised, open-label, phase 3 trial
Bevacizumab and platinum-based combinations for recurrent ovarian cancer: a randomised, open-label, phase 3 trial
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DOI：
10.1016/s1470-2045(20)30142-x
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发表时间：
2020-05-01
期刊：
影响因子：
51.1
通讯作者：
Kurtz, Jean-Emmanuel
中科院分区：
文献类型：
--
作者：
Pfisterer, Jacobus;Shannon, Catherine M.;Kurtz, Jean-Emmanuel
背景适合铂类再治疗的复发性卵巢癌的最新疗法包括含贝伐珠单抗的联合治疗（例如，贝伐珠单抗联合卡铂紫杉醇或卡铂吉西他滨）或最有效的非贝伐珠单抗方案：卡铂聚乙二醇脂质体多柔比星。这个头对头试验的目的是比较一个标准的贝伐单抗含方案与卡铂聚乙二醇脂质体多柔比星结合bevacizumab.Methods这个多中心，开放标签，随机，3期试验，在159个学术中心在德国，法国，澳大利亚，奥地利和英国。符合条件的患者（年龄>= 18岁）患有组织学证实的上皮性卵巢癌、原发性腹膜癌或输卵管癌，一线铂类化疗后首次疾病复发超过6个月，东部肿瘤协作组体能状态评分为0-2。患者按停铂间期、残留肿瘤、既往抗血管生成治疗和研究组语言进行分层，并按1：1使用大小为2、4或6的随机排列区组，接受6个贝伐单抗静脉给药周期（15 mg/kg，第1天）+卡铂（浓度曲线下面积[AUC] 4，第1天）+吉西他滨（1000 mg/m（2），第1天和第8天）每3周一次或6个周期的贝伐珠单抗（10 mg/kg，第1天和第15天）+卡铂（AUC 5，第1天）+聚乙二醇化脂质体阿霉素（30 mg/m2，第1天），随后维持贝伐珠单抗（两组均为15 mg/kg，每3周一次），直至疾病进展或不可接受的毒性。在这项开放标签试验中没有设盲。主要终点是根据实体瘤疗效评价标准第1.1版评估的无进展生存期。在意向治疗人群中分析疗效数据。在接受至少一剂研究药物的所有患者中分析安全性。这项已完成的研究在ClinicalTrials.gov注册，NCT 01837251。结果在2013年8月1日至2015年7月31日期间，682名合格患者入组，其中345名随机分配接受卡铂聚乙二醇化脂质体多柔比星贝伐珠单抗（实验组），337名随机分配接受卡铂吉西他滨贝伐珠单抗（标准组）。数据截止日期（2018年7月10日）时，试验组中位无进展生存期随访时间为12.4个月（IQR 8.3-21.7），标准组为11.3个月（8.0-18.4）。实验组的中位无进展生存期为13.3个月（95% CI 11.7-14.2），标准组为11.6个月（11.0-12.7）（风险比0.81，95% CI 0.68-0.96; p=0.012）。最常见的3级或4级不良事件是高血压（实验组332例患者中的88例[27%] vs标准组329例患者中的67例[20%]）和中性粒细胞减少症（40例[12%] vs 73例[22%]）。实验组332例患者中有33例（10%）发生严重不良事件，标准组329例患者中有28例（9%）发生严重不良事件。实验组有1例患者发生治疗相关死亡（
Background State-of-the art therapy for recurrent ovarian cancer suitable for platinum-based re-treatment includes bevacizumab-containing combinations (eg, bevacizumab combined with carboplatin paclitaxel or carboplatin gemcitabine) or the most active non-bevacizumab regimen: carboplatin pegylated liposomal doxorubicin. The aim of this head-to-head trial was to compare a standard bevacizumab-containing regimen versus carboplatin pegylated liposomal doxorubicin combined with bevacizumab.Methods This multicentre, open-label, randomised, phase 3 trial, was done in 159 academic centres in Germany, France, Australia, Austria, and the UK. Eligible patients (aged >= 18 years) had histologically confirmed epithelial ovarian, primary peritoneal, or fallopian tube carcinoma with first disease recurrence more than 6 months after first-line platinum-based chemotherapy, and an Eastern Cooperative Oncology Group performance status of 0-2. Patients were stratified by platinum-free interval, residual tumour, previous antiangiogenic therapy, and study group language, and were centrally randomly assigned 1:1 using randomly permuted blocks of size two, four, or six to receive six intravenous cycles of bevacizumab (15 mg/kg, day 1) plus carboplatin (area under the concentration curve [AUC] 4, day 1) plus gemcitabine (1000 mg/m(2), days 1 and 8) every 3 weeks or six cycles of bevacizumab (10 mg/kg, days 1 and 15) plus carboplatin (AUC 5, day 1) plus pegylated liposomal doxorubicin (30 mg/m2, day 1) every 4 weeks, both followed by maintenance bevacizumab (15 mg/kg every 3 weeks in both groups) until disease progression or unacceptable toxicity. There was no masking in this open-label trial. The primary endpoint was investigator-assessed progression-free survival according to Response Evaluation Criteria in Solid Tumors version 1.1. Efficacy data were analysed in the intention-to-treat population. Safety was analysed in all patients who received at least one dose of study drug. This completed study is registered with ClinicalTrials.gov, NCT01837251.Findings Between Aug 1, 2013, and July 31, 2015, 682 eligible patients were enrolled, of whom 345 were randomly assigned to receive carboplatin pegylated liposomal doxorubicin bevacizumab (experimental group) and 337 were randomly assigned to receive carboplatin gemcitabine bevacizumab (standard group). Median follow-up for progression-free survival at data cutoff (July 10, 2018) was 12.4 months (IQR 8.3-21.7) in the experimental group and 11.3 months (8.0-18.4) in the standard group. Median progression-free survival was 13.3 months (95% CI 11.7-14.2) in the experimental group versus 11.6 months (11.0-12.7) in the standard group (hazard ratio 0.81, 95% CI 0.68-0.96; p=0.012). The most common grade 3 or 4 adverse events were hypertension (88 [27%] of 332 patients in the experimental group vs 67 [20%] of 329 patients in the standard group) and neutropenia (40 [12%] vs 73 [22%]). Serious adverse events occurred in 33 (10%) of 332 patients in the experimental group and 28 (9%) of 329 in the standard group. Treatment-related deaths occurred in one patient in the experimental group (